N-(heteroarcyclic)piperazinylalkyl-azaspiroalkanediones

ABSTRACT

THE PRESENT INVENTION CONCERNS THE CLASS OF HETEROCYCLIC CARBON COMPOUNDS COMPRISED OF N-(HETEROARCYCLIC)PIPERAZINYLALKYL DERIVATIVES OF AZASPIROALKANEDIONES WHICH HAVE POTENT AND SPECIFIC TRANQUILIZING ACTION AND ANTIEMETIC PROPERTIES. FURTHER, THIS INVENTION IS CONCERNED WITH THE SYNTHETIC PROCESS FOR THE PREPARATION OF N-(HETEROARCYCLIC)PIPERAZINYLALKYLAZASPIROALKANEDIONES WHICH COMPRISES REACTION OF SPIRO-SUBSTITUTED GLUTARIC ANHYDRIDE OR IMIDE WITH N(HETEROARCYCLIC)PIPERAZINE DERIVATIBES. TYPICAL EMBODIMENTS OF THIS INVENTION ARE 8-(4(4-(2-PYRIMIDINYL)-1-PIPERAZINYL)-BUTYL)-8-AZASPIRO(4.5) DECANE-7,9-DIONE AND 8-(4-(4-(2-PYRIDYL)-1-PIPERAZINYL)) BUTYL)-8-AZASPIRO(4,5) DECANE-7,9-DIONE.

United States Patent C ice 3,717,634 N-(HETEROARCYCLIC)PIPERAZINYLALKYL-AZASPIROALKANEDIONES Yao Hua Wu and James W. Rayburn, Evansville, Ind,assignors to Mead Johnson & Company, Evansville,

Ind. No Drawing. Filed Nov. 24, 1969, Ser. No. 879,604 Int. Cl. C07d /42US. Cl. 260-4564 N 7 Claims ABSTRACT OF THE DISCLOSURE SUMMARY OF THEINVENTION This invention relates to new compounds characterized by thefollowing general structural formula and the nontoxic pharmaceuticallyacceptable acid addition salts thereof.

Formula I In the foregoing Formula I, n is the integer 4 or 5. Thesymbol -A which connects the spiroglutarimide and theN-(heteroarcyolic)piperazine represents a divalent alkylene chain of 2to 6 carbon atoms inclusive. Said alkylene chain can be straightorbranched-chain hydrocarbon grouping in which the ring connecting bondsare on different carbon atoms such as hexamethylene (CH2 CH2 CH2CHCHzCHz) 2-methyl-1,2-propylene OH2C and the like. The piperazinesubstituent represented by the symbol B is selected from the groupconsisting of imidazoyl and a heteroarcyclic. Said heteroarcyclic isrepresented by the symbol:

I WWY Na 3,717,634 Patented Feb. 20,. 1973 wherein W and Y areindependently selected from th group consisting of CH and nitrogen. Bythe term heteroancyclic as used herein, it is meant substituentscomprised of nitrogen, carbon, and hydrogen which when taken togetherform a heteroaromatic system. The R and R substituents of theheteroarcyclic referred to above are independently selected from thegroup consisting of hydrogen, lower alkyl from 1 to 4 carbon atomsinclusive, alkoxy of from 1 to 4 carbon atoms inclusive, hydroxy, amino,alkylthio of 1 to 4 carbon atoms inclusive, halogen, trifiuoromethyl,alkanoamido of from 1 to 6 carbon atoms inclusive, and alkanesulfonamidoof 1 to 6 carbon atoms inclusive. By the term lower alkyl as employedherein it is meant straight or branched chain alkyl radicals includingmethyl, ethyl, propyl, isopropyl, l-butyl, l-methylpropyl,Z-methylpropyl, and tert.-butyl. Similarly, the alkyl fragment of thealkylthio substituent refers to straight or branched chain radicalsdescribed above. Straight or the branched chain alkanes of 1 to 6 carbonatoms inclusive comprise the alkane radical of alkanoamido andalkanesulfonamido groupings.

The term non-toxic pharmaceutically acceptable acid addition salts asused herein refers to a combination of compounds of the presentinvention with relatively nontoxic inorganic or organic acids.Illustrative of the variety of acids which may be used are sulfuric,phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic,methanesulfonic, benzenesulfonic, para-toluenesulfonic, acetic, lactic,succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic,cinnamic, and related acids.

Conversion of the compounds of the present invention to pharmaceuticallyacceptable acid addition salts is accomplished by admixture of thesecompounds with substantially one chemical equivalent of any of thevarious acids hereinbefore defined. Generally the reactions are carriedout in an inert solvent. Suitable solvents, merely by way of example,are ethanol, benzene, ethyl acetate, ether, and halogenatedhydrocarbons.

Illustrative of the nomenclature employed herein for the naming of theproducts of this invention are partial structures corresponding to thesubstituted glutarimide portions of Formula I are shown below with thepositions numbered.

| a 7 a 4 e 8-Azaspiro[4.5]decane-7, 9-dione Formula I, n=4

3-Azaspiro[5.5]undeca.ne-2, 4-dioue Formula 1, n=5

General embodiments of the process for the preparation of compounds ofthe present invention are schematically illustrated below and labeledMethod A, Method B and Method C. The use of a particular method toproduce compounds embraced by this invention is dietated to a largeextent by conditions which will be apparent to those skilled in the art.In practice, the selection of the method used for the preparation of anyone compound of the present invention is principally determined by thecommercial availability of the necessary intermediates and/or by thecase which available compounds can be converted to desiredintermediates.

METHOD A O (W HzN-A-N NB Formula I Formula II Formula III METHOD B(4112) N-A-X HN NB FormulaI Formula IV Formula V METHOD C i H2) N-MX-A-N NB FormulaI Formula VI Formula VII In the foregoing reactionschemes, the symbols n, -A, and B have the same meanings as previouslydefined relative to Formula I. The symbol X refers to the acid residueof a reactive ester grouping such as a chloride, bromide, iodide,sulfate, phosphate, tosylate or mesylate. M comprises an alkali metalsalt of the substituted glutarimide and is preferably sodium orpotassium.

Method A is carried out by reacting a spiro-substituted glutaricanhydride of Formula II with the l-(w-aminoalkyl) 4(heteroarcyclic)piperazines of Formula III to provide products ofFormula I. Preferably, the reaction is carried out at elevatedtemperatures in a reaction inert organic solvent. By the term inertorganic solvent, as referred to herein is meant any protic or aproticsolvent or diluent which does not enter into the reaction to anysubstantial degree. Pyridine is the preferred solvent. Temperatures ofabout 100 C. to about 200 C. are preferred to facilitate completion ofthe reaction. The duration of the reaction is critical only to theextent of providing maximum yields and reaction periods of from about 16hr. to as much as 11 days are preferred. The lengthy reaction periodsare necessary in some instances to obtain complete conversion ofglutaric acid half-amides of Formula VIII which are initially formedwhen an anhydride of Formula II is combined with an amine of FormulaIII.

i rins NHAN NB o-orr Formula VIII The glutaric acid half-amides ofFormula VIII may be also transformed into Formula I products by heatingin boiling acetic anhydride which is a well known standard organicprocedure for ring closure useful in the formation of cyclic imides.

Method B is carried out under reaction conditions amply described inliterature wherein teritary amines are formed by alkylation of asecondary amine with an alkyl halide, sulfate, phosphate, tosylate, ormesylate. The Formula IV and Formula V intermediates are preferablyreacted in an inert liquid reaction medium at temperatures of from about60 C. to about 200 C. in the presence of a base suitable for use as anacid binding agent. Sodium carbonate is a particularly preferred acidbinding agent but other inorganic and tertiary organic base may beemployed including other alkali and alkaline earth metal carbonates,bicarbonates, or hydrides and tertiary amines. Reaction periods rangingfrom about 2 hrs. to approximately 4 days are preferred in order toobtain satisfactory yields of the present compounds. A particularlypreferred solvent is n-butanol but any inert reaction medium isgenerally applicable to use in this reaction. To a large extent, theduration of the reaction period depends upon the temperature andreaction solvent selected. By way of illustration, alkylation isfacilitated and the reaction period is appreciably shortened ifdimethylformamide is employed as the reaction medium compared to asolvent such as benzene.

Method C is another method useful for preparation of compounds ofFormula I. In this method, the spiroglutarirnide metal salt depicted byFormula VI is reacted with substituted piperazines of Formula VII.Standard laboratory procedures are employed in carrying out the reactionsuch as those described for the alkylation step of the Gabrielsynthesis-S. Gabriel, Ber. 20, 2224 (1887). For example, the reactantsare combined in an inert reaction medium at temperatures ranging fromabout 25 C. to 200 C. Preferred solvents for carrying out the reactionare dimethylformamide, acetone, benzene, n-butanol, ethanol and thelike.

With respect to the reactants for Methods A, B and C, many of them,including 3,S-tetramethyleneglutaric anhydride, (Formula II, 11:4) areknown compounds which are readily available from commercial sources.Others, which are not commercially available, can be prepared inaccordance with standard synthetic procedures which are known to thoseskilled in the art.

Preparation of N (heteroarcyclic)piperazines of Formula V have beendescribed by K. L. Howard at al. in J. Org. Chem., 18, 1484 (1953).Their procedures are applicable to the preparation of otherN-(heteroarcyclic)piperazine intermediates not specifically disclosedbut which are required for the preparation of compounds embraced in thepresent invention.

The l-(w-aminoalkyl)-4-(heteroarcyclic)piperazine of Formula III areobtained according to methods described in U.S. Pat. 3,398,151 byalkylation of N- (heteroarcyclic)piperazines of Formula V withhaloalkylnitriles to provide 1 (w cyanoalkyl) 4(heteroarcyclic)piperazine intermediates which are subsequently reducedto the Formula III substituted piperazines. Reduction of the cyanointermediate may be carried out catalytically, preferably with W-6 RaneyNickel catalyst under high pressure, or alternatively with hydrazine andW-6 Raney Nickel.

The intermediate azaspirodecane-and undecanediones of Formula IV havingthe -A-X- group attached to the nitrogen atom are prepared according toprocedures described in U.S. Pat. 3,398,151. Reaction 'of the glutaricanhydrides of Formula II with an alkanolamine of the formula H NAOH arecarried out under conditions similar to those described hereinabove forMethod A. The resulting intermediate .g'lutarimide has the structureshown for Formula IV wherein X is OH. Esterification of this material isaccomplished by conventional techniques well known to the art to providethe intermediate of Formula IV. Preferably, thionyl chloride is reactedwith the alcohol precursor of Formula 1V (X=OH) to provide theintermediate wherein X is chlorine. Conventional techniques which areadequately described in the literature are employed to provide thebromides, iodides, phosphates, sulfates, tosylates, and mesylatescorresponding to Formula IV.

The piperazine reactant of Formula VII having the X-A- grouping attachedto the nitrogen atom is prepared according to standard organicprocedures. By way of example, reaction of the piperazines of Formula Vwith alkanol halides of the Formula HOA-X proides intermediate ofFormula VIII.

Formula VIII This intermediate is then esterified according toconventional techniques well known to the art to provide the Formula VHreactants. For instance, thionyl chloride acting upon the compounds ofFormula VIII provides the Formula VII intermediate in which X ischlorine. In a similar fashion, bromides, and iodides are prepared.Phosphates, sulfates, tosylates, mesylates corresponding to Formula VIIare obtained with conventional laboratory techniques.

General embodiments of the process of the present invention for thepreparation of compounds of Formula I as hereinabove described areconsidered to be a unitary process. Thus, the azaspiroalkanedione ofFormula I are prepared in accordance with the unitary process of thepresent invention by reacting a piperazine of the Formula Y-bi NBFormula IX wherein Y is selected from the group consisting of hydrogen(Formula IXa), H 'NA- (Formula IXb), or XA-- (Formula IXc), and A and Xare as hereinbefore defined, with a spirO-glutaric acid anhydride ofFormula II.

( fl) n X Formula II wherein n is as hereinbefore defined, when Y is thegroup H N-A-; or a N-substituted spiro-glutaric acid imide of FormulaIV.

( C Hz) 21 X N-A-X Formula IV wherein A and n are as hereinbeforedefined and X is a reactive ester group, when Y is hydrogen; or aspiroglutarimide of Formula VI.

Formula VI tion. In the instant case, it has been discovered that N-(heteroarcyclic)piperazine alkyl derivatives of azaspirodecanediones andazaspiroundecanediones are highly active and specific tranquilizingagents and in addition also exhibit anti-emetic properties. Presentcompounds are improved tranquilizing agents compared to theazaspirodecanediones and azaspiroundecanediones of United States Pat.3,398,151, in that tranquilizing activity is more potent and specific.

With respect to side effects such as sedative and alphaadrenergicblockade which are exhibited by a number of prominent tranquilizingagents the present compounds are unique in that such adverse reaction issubstantially diminished or practically non-existent. By way ofillustration, 8- [4- [4-(2-pyrimidinyl)-1-piperazinyl]butyl]- 8azaspiro[4.5]decane-7,9 dione hydrochloride has only about thealpha-adrenergic blocking activity of the well known tranquilizer,chloropromazine.

Tranquilizing properties of the compounds of this invention can bedemonstrated in rats by a shuttle box technique described by I. R.Albert and L. E. .Allen in the Ph'armacologist 4, '152 (1962). This testis designed to differentiate tranquilizing agents from non-specificcentral nervous system depressants such as sedatives and hypnotics.Tranquilizing effects are observed when the compounds of the presentinvention are administered intraperitoneally to the rat in dosagesranging from 1.5 to mg./kg. of body weight.

The tranquilizing action of the compounds of the present invention canbe demonstrated in Rhesus monkeys by observing general behavioraleffects. Intramuscular administration of present compounds to the monkeyin dosages ranging from 2 to 16 mg./kg. of body Weight affordstranquilizing effects similar to those produced by chlorpromazine.

The compounds of the present invention are relatively non-toxiccompounds. For example, the intraperitoneal 50% lethality dose of 8 [4[4 (2pyrimidinyl)- 1 piperazinyl1butyl] 8 azaspiro[-4.5]decane-7,9-dionehydrochloride is 146 mg./kg. of body weight in the mouse.

Systemic administration of the compounds of the present invention tomammals in dosages ranging from about 0.01 to 40 mg./kg. of body weightper day induce effective tranquilizing responses in the mammalianrecipient. Oral, parenteral and rectal routes are preferred forms ofsystemic administration. Forms of parenteral administration includeintramuscular, intravenous, and subcutaneous administration. Thoseskilled in the art will recognize that the dosage of the compounds ofthe present invention will vary with the form and mode of administrationand in some instances with the particular compound chosen. Generally, itwill be found that when a compound of the present invention isadministered orally, a larger quantity of the active agent is requiredto produce the same effect as a smaller quantity thereof which is givenparenterally. It is generally preferred to administer the compounds ofthis invention at a concentration level that will produce effectivetranquilizing effects without causing any harmful or deleterious sideeffects.

For pharmaceutical purposes, the compounds of Formula I may beadministered to mammals in the form of free bases or in the form ofnon-toxic acid addition salts. In the free base form, the compounds arerelatively insoluble in water but are soluble in most organic sol ventssuch as lower alkyl alcohols, esters, acetones, chloroform and the like.The present compounds in the form their acid addition salts are, ingeneral, soluble in water and methanol but relatively insoluble insolvents such as benzene, ether, petroleum ether and the like. In eitherthe free base or the acid addition salt form, the compounds of Formula Imay be compounded and formulated into pharmaceutical compositions andunit dosage suitable for systemic administration. Organic or inorganicExamples of representative compounds of the present invention preparedaccording to Procedure 1 are indicated in Table I.

TABLE I.-8-[4(N-HETEROARCYCLIC)-l-PIPERAZINYLALKYIJ-B-AZASPIRO[4.51DECANE-73-DIONEPRODUCTS Product Base Hydrochloride Analyses Ex. B.P., 0. Percent No.Method 11 Hot. (mm. g) yield M.P., O. Crystn.solvent Formula C H N Cl 1A 2 208 -2U9 5 Eula-I101 CzoHggN4Og-HC1 61.11 7.25 14.26 8.81

2 A 4 Same as above (a 76 172173.5 Z-butanone C H Mm-HCI 63.01 7.8913.55 8.29

N 3 2 2302 90 200207 Absolute ethanol CnHzrNsOa-HCI 58.00 7.23 17.750.03

4 B 3 Same as above 214-215 Absolute ethanol-amen. CzoHzpNgOrHCl 59.067.30 17.24 l- 5 A i do 61 201.5-20215 Absolute ethanol ommlmol-nci 60.297.41 16.60 8.48 s A 5 do 23 39 52 188.5190.5 Methanolethyl acetate"caramel-H01 60.44 7.93 10.01

7 B 3 23 59 mas-234.5 Ethanol oflnammnm 00.12 7.73 13.01 7.98

CHzO

used herein it is meant forms of administration such as METHOD B oral,parenteral and rectal. Pharmaceutical compositions considered within thescope of this invention may take the form of tablets, powder, granules,capsules, suspensions, solutions, suppositories, elixirs, ointments andthe like. Unit dosages ranging from about 1 to 500 mg. are employed.Suitable pharmaceutical carriers comprise both solids and liquids suchas corn starch, lactose, calcium phosphate, stearic acid, polyethyleneglycol, water, sesame seed oil, peanut oil, propylene glycol, and thelike.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples areillustrative of the process and products of the present invention andare not to be construed as limitations of this invention, manyvariations of which are possible without departing from the spirit andscope thereof.

METHOD A Procedure l.-Condensation with Substituted Glutaric Anhydride.Amixture of 0.1 mole of the substituted glutaric anhydride (Formula II),0.1 mole of l-(w-aminoalkyl) 4 (heterocycle)piperazine (Formula 111),and 300 ml. of pyridine is refluxed until imide formation is complete.The degree of reaction is readily followed by taking an aliquot portionof the reaction mixture, removing the solvent, and obtaining theinfrared absorption spectrum of the residue. When reaction is complete,the spectrum exhibits typical infrared imide bands at 1700 and 1710 cm?whereas if incomplete, the infrared spectrum contains amide and carboxylabsorption bands at 1680, .1760, and 3300 cm.-

The azaspiroalkanedione product is purified as the free base bystripping oi the pyridine solvent and crystallizing the residue from asuitable solvent or by vacuum distillation thereof.

Suitable acid addition salts of the product are prepared by treating anethanol solution of the free base with an equi-molar amount of theappropriate acid.

Procedure 2.-Alkylation of N(heteroarcyclic)piperazines.-A mixture of4.9 g. (0.02 mole) of 8-[3- chloro- 1-propyl)-8-azaspiro [4.5]decane-7,9di0ne, 3 .3 g. (0.02 mole) prepared in the manner of US. Pat.3,398,- 151, N-(2-pyrimidyl)piperazine, and 2.2 g. (0.02 mole) of sodiumcarbonate in 75 ml. of n-butanol is refluxed for three days andfiltered. The filtrate is concentrated in vacuo and the residue taken upin ml. of benzene. Addition of 4.0 ml. of 5.0 N ethanolic hydrogen chloride to the benzene solution of the free base provides the product8-[3-[4-(2-pyrimidinyl)-l-piperazinyllpropyl]-8-azaspiro[4.5]decane7,9-dioneas a hydrochloride salt which is collected and crystallized fromabsolute ethanol-ether, yield 3.4 g., M.P. 214-215 C. (corn).

Examples of representative products of this invention and physicalproperties thereof prepared according to Method B are listed in Table 1.

METHOD C Procedure 3.Alkylation of Azaspiroalkaneimides.-- A solution of0.1 mole of 3,3-tetramethyleneglutarimide in methanol ml.) is treatedwith 0.1 mole of sodium methoxide. The solvent is removed in vacuo toprovide a residue consisting of the sodium salt of3,3-tetramethyleneglutarimide which without further purification iscombined with 0.1 mole of 1-(2-chlorobutyl)-4-(pyrimidiny1) piperazinein 150 ml. of n-butanol. The mixture is refluxed for a period of time ofsufiicient duration to provide approximately 0.1 mole of precipitatedsodium chloride as a by-product. Isolation of the product by standardlaboratory procedures provide 8-[3-[4-(2-pyrimidinyl)-lpiperazinyl1propyl1-8 azaspiro[4.5]decane 7,9-dione which is also aproduct of Procedure 2.

Examples 8-28.Additional exemplification of compounds of the presentinvention is given in Table II along with the mode of preparationaccording to Method A, Method B, or Method C and the appropriateintermediates. Although only a single method of preparation TABLEII-Contlnued Product Ex. No. 11 A Het. Method Intermediates 21 4 (CHz)4-O-C(CH;); B 8-(4-ehlorobutyl)-8-azaspir0I4.5]decane-7,9-dlone andl-[2-(4-tert.-butylpyrimidinympiperazine.

22 4 -(CH1)4- B 8-(4-chlorobutyl)-8-azaspiro[4.5]decane-7,Q-dione and1-[2-(6-trlfluoromethylpyridinympiperazine.

23....- 4 -(CH=); N A 3,3-tetramethyleneglutar1e anhydrlde and1-(4-aminobutyD-4-[2-(1,3,5-

N triazinyl)]piperazine.

24"-.. 4 (CH NO; C 3, B-t-etramethyleneglutarimlde and1-(2-chloroethyl)4-[2-(4-nltm4, 3, 5-

N mazinympiperazine.

25.-- 4 (CHz)4- N A 3, 3-tetramethyleneglutarlc anhydride and1-(4-aminobutyD-4-[2-(3-propionylamidopyridinyb]piperazine.

NH 0 01H;

26..." 4 (CH:) NHSOICH; A 3, 3-tetramethyleneglutarlc anhydride and1-(4-amlnobutyl) -4-[4-(2, 6

dimethanesulfonamidopyrimidinyl)1p1perazine. N.-

NHSOaCHa 27-.." 4 (OH )4 N A 3, a-tetramethyleneglutarlc anhydride and1-(4-amlnobutyl)-4-[2-(4-hydroxy- H pyrimldinyl) piperazine.

28..-" -(CHa)4- A 3, s-pentamethyleneglutaric anhydride and1-(4-aminobutyD-4-(2-pyridinybpiperazine.

8[4-[4-(4,6dimethyl-2-py1imidinyl)-l-piperazinyllbntyll-ileazaspiro[4.5]decane-7,Q-dionehydrochloride. M.P. 216.5217.5 0. (corn), crystallized from absoluteethanol-anhydrous ether. Analysis-Salad. for CzaHauClNaOz! C, 61.38; H,8.06; N, 15.56. Found: C, 61.26; H, 8.10; N, 15.53.

Procedure 4.1-(3cyanopropyl)-4-(2 pyrimidinyl)- piperazine.-A mixture ofl-(2-pyrimidinyl)pipera2ine (6.0 g., 0.04 mole), 4.6 g., (0.044 mole) of3-chloropropionitrile and sodium carbonate (4.24 g., 0.04 mole) in m1.of n-butanol is gently refluxed for 16 hours. The reaction mixture isconcentrated in vacuo and the residual oil dissolved in about 100 ml. ofcyclohexane.

On standing a white crystalline material separates which is crystallizedfrom cyclohexane to provide 6.5 g. (yield of the cyano intermediate,M.P. 56.658 C. Representative examples of cyano intermediates useful inProcedure 5 along with information relative to the preparation thereofaccording to Procedure 4 are listed in Table III.

TABLE III.-1-(w-C YANOALKYL) 1(HETE ROABC YCLIC) PIPE RAZINES AnalysisIntermediate B.P., 0.

number Hats 11 Yield (mm. Hg) M.P., 03" Formula C H N 1 1 32 u uN4 sameas abm 3 92 %?85} 1 47-49 0.3mm.

3 1 8O 1 98400 CmHnNs 59. 12 6. 62 34. 77

4 Same as above 3 7O 1 56-58 CnHuH; 2.04 7.31 30.08 5- do 4 80 1 77-78C15H19N5 63.49 7. 62 28. 41

6 NH, 3 87 5 191-192 CflHflN? 37.84

TABLE IIICntlnued Analysis Intermediate B.P., 0. number Het 11 Yield(mm. Hg) M.P., 0. Formula C H N 7 CHBO a 46{ ounflmo, 56.90 1.01 23.41

CHgO

3 uooj 109-110 CiaHmNu 59.94 7.66 32.48

1 Crystalline solvent is cyclohexane.

2 Crystalline solvent is methanol.

! Crystalline solent is ethyl acetate-Skellysolve F. 4 Crude.

Procedure 5.1-(4-aminobutyl) 4 (2 pyrimidinyl) piperazine.(A) A solutionof 11.5 g. (0.05 mole) of 1-(3-cyanopropyl)-4-(2-pyrimidinyl)piperazinein 150 ml. of absolute ethanol is saturated with ammonia. W-6 Raneynickel catalyst is added and the mixture hydrogenated under 1200 psi.When the hydrogenation is completed the mixture is filtered and theresidual oil distilled under reduced pressure to provide 8.2 g. (70%) ofl-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine.

Reduction of cyano intermediates of Procedure 4 in the manner describedfor Procedure 5 or alternatively by reduction with hydrazine and Raneynickel provide the amino intermediates of Formula III. The followingprocedure is illustrative of hydrazine and Raney nickel reductions.

(B) Hydrazine hydrate 85% (640 ml.) is added drop- Wise to4-[4-(2-pyrimidinyl) l piperazinylJbutyronitrile (189.8 g., 0.82 mole),Raney nickel (190 g.Wet with water, activated by washing with2-propanol) and 2-propanol (1.4 liter) in 2 hours at reflux. Thereaction is stirred for 5 minutes, filtered, concentrated in vacuo andthe residual material distilled to yield 168.2 g. (87%) of1-(4-aminobutyl)-4-(Z-pyrimidinyl)piperazine, B.P. 143- 6" C. at 0.1 mm.(11 15582).

Procedure 6.Solution for parenteral injection-The azaspiroalkanedionecompounds of the present invention are formulated for parenteraladministration according to the following example. A sterile solutionsuitable for intravenous injection is prepared by dissolving 21.9 g. of8-[4- [4-(2-pyrimidinyl) 1 piperazinyl]butyl] 8azaspiro[4.5]decane-7,9-dione hydrochloride in 2 liters of water forinjection, USP. The solution is adjusted to pH 4.2 with 0.1 N-sodiumhydroxide. After adjusting the pH, the solution is sterilized by passagethrough a bacteriological filter and ml. glass ampules asepticallyfilled in order to provide 10 mg. of active ingredient per ampule.

Procedure 7.Tablets.The azaspiroalkanedione compounds of the presentinvention are compounded into tablets in accord with the followingexample.

Material: Amount, grams 8-[4-[4-(2 pyrimidinyl) 1 piperazinyHbutyl]-8-azaspiro [4.5 decane-7,9-dione hydrochloride 54.8 Magnesium stearate1.3 Corn starch 12.4 Corn starch pregelatinized 1.3 Lactose 180.2

a compound having the formula n is the integer 4 or 5;

A is a divalent straight or branched alkylene chain of 2 to 6 carbonatoms inclusive and connects the nitrogen atoms as shown through atleast 2 carbon atoms;

B is

wherein one of W and Y is CH and the other is nitrogen,

R and R are independently selected from the group consisting ofhydrogen, lower alkyl from 1 to 4 carbon atoms inclusive, and loweralkoxy of from 1 to 4 carbon atoms inclusive;

References Cited UNITED STATES PATENTS 8/1968 Yao Hua Wu 260-268 PHOTHER REFERENCES Howard et al., J. Org. Chem. 18, 1484 (1953).

ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner U.S. Cl. X.R.

